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Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent 'ene'-reductases.


ABSTRACT: Flavin-dependent 'ene'-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. Although these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyse reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here, we demonstrate that these enzymes can catalyse redox-neutral radical cyclizations to produce enantioenriched oxindoles from ?-haloamides. This transformation is a C-C bond-forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground-state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous ?-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

SUBMITTER: Black MJ 

PROVIDER: S-EPMC6925616 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Asymmetric redox-neutral radical cyclization catalysed by flavin-dependent 'ene'-reductases.

Black Michael J MJ   Biegasiewicz Kyle F KF   Meichan Andrew J AJ   Oblinsky Daniel G DG   Kudisch Bryan B   Scholes Gregory D GD   Hyster Todd K TK  

Nature chemistry 20191202 1


Flavin-dependent 'ene'-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. Although these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyse reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here, we demonstrate that these enzymes can catalyse redox-neutral radical cyclizations to produce enantioenriched oxindoles from α-haloamides. This transformation is a C-C bond-fo  ...[more]

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